Combined Targeting Of Akt And Mek With The Akt Inhibitor Gdc-0068 And Mek Inhibitor Gdc-0973 Demonstrates Synergistic Anti-Tumor Effects

Background: Akt, a serine/threonine protein kinase, and MEK, a dual specificity kinase, are key signaling nodes in the PI3K/Akt/mTOR and the Ras/Raf/MAPK pathway, respectively. Both Akt and MEK play key roles in regulating numerous cellular processes such as cell proliferation, growth, survival, protein synthesis and oncogenic transformation. Many cancer types have alterations in both of these pathways and inhibiting only one of these pathways can result in up-regulation of the other pathway. We previously reported on a potent highly selective ATP-competitive pan-Akt inhibitor, GDC-0068 as well as a potent selective inhibitor of MEK, GDC-0973 that are currently in Phase 1 clinical trials. We hypothesized that dual inhibition of both MEK and Akt pathways with the combination of these two agents would induce synergistic antitumor activity. Methods: In these studies, we evaluated the efficacy of GDC-0068 and GDC-0973 both individually and in combination on a panel of cancer cell lines. Cells were treated with either GDC-0068 or GDC-0973 or in combination at increasing concentrations and assayed after 4 days for viability. For in vivo studies, tumor cells were subcutaneously implanted in the flank of female NCR.nude mice. Once tumors reached sufficient size, mice were dosed orally for 21 days with GDC-0068, GDC-0973 or the combination of both compounds. Results: In vitro, the combination of GDC-0068 and GDC-0973 results in enhanced inhibition of cell viability compared to either single agent alone. Synergistic effects are observed in multiple cell lines; especially in cell lines that have activation of the Ras/Raf/MAPK pathway or both pathways (e.g. via the combination of PTEN loss or PI3K mutations and Ras or BRaf mutations). Combined knockdown of downstream targets of both Akt and MEK is observed at concentrations where a synergistic effect is observed, with enhanced knockdown of several converged targets. Increased cell death is also observed. These results were recapitulated in vivo in xenograft models, where the combination of GDC-0068 and GDC-0973 resulted in increased tumor growth inhibition or regression compared to either single agent alone. All combinations tested were well tolerated as assessed by animal body weights and mortalities. Conclusions: Our studies demonstrate significant combination benefit between GDC-0068 and GDC-0973 on cell viability in vitro and tumor growth in vivo. These data support the clinical development of the combination of these two compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 873. doi:1538-7445.AM2012-873